Introduction

Any of several
diverse pathways might be used to develop molecular manufacturing. There are
many strategies, techniques, and tools that may contribute to its development.
Further study will be needed to decide which approach is best. Questions to be
answered for each approach include the effort required to develop it, the
performance (throughput and cost) of the manufacturing system, and the
performance of the products.

2Exponential molecular manufacturing: The ability to use molecular
manufacturing systems to build additional usable molecular manufacturing
systems, making it possible to produce large quantities of product.

The first
milestone has almost been achieved already; the principle has been demonstrated
in the laboratory. This level of technology may be used to make
sensors, as well as a variety of research tools, and possibly to make limited
but useful quantities of pharmaceuticals.

The requirements
to move from the first to the second milestone can be identified and preliminary
design work can be started today. The ability to build large quantities
of individually constructed molecularly precise products would be extremely
valuable. Potential products include computers, pharmaceuticals, medical tools,
and advanced materials.

Moving from the second to the third milestone would greatly increase the range
of possible products. It has been argued elsewhere that this step might not be
prohibitively difficult[i].
However, the engineering details will depend on the molecular manufacturing
technology being used, which could vary widely.

After exploration of the range of options for developing these capabilities,
several specific areas for study are suggested. These studies, which could be
initiated today, would help to quantify the potential of the technology and the
effort required to develop that potential.

Basic Molecular
Manufacturing

The individual control of molecular composition and placement is often cited as
a goal of nanotechnology. To date, many nanotechnology efforts have been content
to achieve nanoscale—but not atomic—precision, or to build large quantities of
small identical molecules. However, there are some technologies that are on the
verge of achieving the goal.

Liao and Seeman have built a nanomachine out of DNA[ii]
that can guide the construction of any of several different strands of DNA; the
product sequence can be chosen by “programming” the machine with other DNA
strands. This is a demonstration of programmable molecular fabrication. A
planned extension to the machine would allow it to build longer and more
interesting strands. Although this machine does not select from among multiple
sites for the reaction, it does select from among multiple potential reactants,
and its product has a precise and programmable molecular structure.

Aono[iii]
developed the ability to transport individual silicon atoms from one place to
another in a covalent crystal, and was even able to automate this to make
two-dimensional patterns. Several other researchers have also used electricity
(fields and/or currents) with scanning probe microscopes to implement reactions
at sites chosen with atomic precision. Hersam[iv]
has removed single selected hydrogen atoms from silicon at room temperature.
Oyabu[v]
has removed and replaced single silicon atoms with purely mechanical force, but
has not yet reported the ability to build multi-atom patterns.

A strategy for easier atomically precise positioning is to separate the possible
deposition sites. For example, a self-assembled repetitive grid could be used to
create widely separated sites that might even be individually accessed optically
for higher throughput. A related strategy is to deposit large molecules into
large receptors that are designed not to bond if misaligned.

There are several possible ways to increase the throughput of molecular
manufacturing without requiring it to build its own tools. If the manufacturing
operation is done with a scanning probe microscope, then an array of MEMS
microscopes like IBM's “millipede”[vi]
could be used. If it is done with molecular tools similar to Liao and Seeman's,
many tools could be created and used in parallel.

Exponential
Molecular Manufacturing

The productivity of individual control of molecules is limited by the small size
of the molecules. A typical scanning probe microscope might weigh two kilograms,
have a size of about 10 cm, and carry out ten automated operations per second.
If each operation deposits one carbon atom, which masses about 2x10-26 kg, then
it would take 1026 seconds or six billion billion years for that scanning probe
microscope to fabricate its own mass!

The speed with which a molecular manufacturing tool can create its own mass of
product may be called “relative productivity.” This depends on several factors:
the mass of the tool, its frequency of operation, and the mass deposited per
operation. Roughly speaking, an object's mass will be about the cube of its
size; hence, for each factor of ten shrinkage, the mass of the tool will decrease by
1,000. In addition, small things move faster than large things, and the
relationship is roughly linear. Taken together, each factor of ten shrinkage of
the tool will increase its relative productivity by about 10,000 times; relative
productivity increases as the inverse fourth power of the size.

If a tool could be shrunk by a factor of a million, from 10 cm to 100 nm, then
its relative throughput could increase by 1024, in which case it would take
only 100 seconds to fabricate its own mass. This assumes an operation speed of
10 million per second (which requires a linear speed of only 2 m/s over a 100 nm
range). This is about ten times faster than the fastest known enzymes (carbonic anhydrase and superoxide dismutase). But a relative productivity of 1,000 or
even 10,000 seconds would be sufficient for a very worthwhile manufacturing
technology. (An inkjet printer takes about 10,000 seconds to print its weight in
ink.)

The following techniques all share a goal of controlling molecular joining
and/or placement in order to build intricate, engineerable, functional,
nanoscale, kinematic systems that are capable of building more of the same. In
general, it is not required that every covalent bond in the final product be
formed under direct mechanical control, or even at the time of the deposition
process. For example, useful molecular building blocks can be pre-built by bulk
chemistry. Also, crosslinking can be triggered optically or chemically after the
manufacturing is completed to increase strength and stiffness.

The goal of building functional manufacturing systems implies that the newly
built systems must be controllable. Many types of control can be broadcast,
including chemicals, photons, pressure, and electric or magnetic fields.
Electric current is harder to broadcast, but systems too small to be contacted
via micromanipulation could self-assemble to electrodes. Electrical control may
ultimately be the fastest and most flexible approach.

Although the techniques can be conveniently divided into groups according to the
working conditions and bonding structure, the divisions between the groups are
not absolute. For example, a system that used liquid xenon as a solvent would
fall halfway between solution-phase and machine-phase.
This reinforces
the point that none of these approaches is entirely distinct from the rest;
there is a continuum from today's well-established techniques to the most
extreme machine-phase proposals.

Polymer Techniques

Ribosomes, which are made of RNA and protein, show that polymers can fold into
functional shapes that carry out manufacturing operations. Polymer sequences can
be controlled digitally by selecting the building blocks in the right sequence,
as ribosomes do, or by flushing different building blocks past while controlling
whether or not they stick, as DNA synthesizers do. Some polymers including DNA
and RNA fold predictably, so their shapes can be engineered. Seeman's machine
selects short sequences to join rather than individual monomers, but a variant
that could select monomers or could be constructed out of a few short repeated
sequences would be able to build a copy of itself.

Polymer chemistry is known to be quite versatile, and it should be possible to
incorporate molecular actuators to select the polymer sequence; this would be
faster and probably more reliable than using DNA strands to program the device.
Molecular actuators can be controlled and powered by light, electricity, or
changes in the composition of the solution.[vii]

Bulk controlled polymerization techniques, such as DNA synthesis, often use two
repeated steps: first they make the end of the polymer reactive by
“deprotecting” it, then add a monomer that is protected from further deposition.
Nanoscale controlled polymerization could control either the timing of the
deprotection step or the monomer selection for the polymerization step. Or the
system could protect the addition site by steric hindrance. Alternatively, it
could use a polymerization reaction that is exothermic but has a high barrier,
and accelerate the desired reaction—possibly by many orders of magnitude[viii]—by
holding the monomer in place. The ratio of reaction rates of confined and
unconfined monomers will approximate the error rate.

Because there is only one reaction site and one choice—to add a monomer or
not—extreme stiffness should not be required in polymer-based molecular
manufacturing systems. Even minimally crosslinked polymers (as shown by the
ribosome) can implement a controllable, low-error system.

Implementing polymer exponential molecular manufacturing systems appears to be a
fairly small step from existing and currently feasible non-exponential
polymer-based polymer-building systems.

Solids Built in
Solution

Instead of building a linear chain that then folds into a shape, it may be
possible to build the desired shape directly by depositing small molecular
building blocks. These building blocks could either form covalent bonds during
deposition, or be held by hydrogen bonds (similar to self-assembly) and perhaps
joined later by crosslinking.

Making an atomically precise product does not require atomic precision in block
positioning—only enough precision to select between adjacent block deposition
sites. Branched molecules, possibly including dendrimers, may be of interest as
building blocks.

This approach has not been much studied yet. It may be worth pursuing because
exotic environments would not be needed, but 3D shapes and structures might be
built directly rather than needing to be formed by folding. Actuator molecules
could either be placed individually or added by self-assembly once the structure
was built.

Any useful moving system needs to have parts moving relative to other parts.
This has not been explored in systems of this class. As in MEMS, springs might
be useful instead of sliding-surface bearings. A wider palette of materials
might allow the spring designs to be more compact. Precise covalent structures
with nanoscale width might be able to bend more sharply without fatigue or
plastic deformation. Another option might be to have monolayer bearings
self-assemble in spaces left during construction. The techniques used in
low-friction biological molecular moving parts (e.g. ATP synthase) might be
useful once they are better understood.

This approach might make use of relatively large molecular building blocks. It
would probably be possible to place large blocks with a relatively crude
scanning probe microscope in order to build the first manufacturing system.
Silicatein, an
enzyme that builds silica, may be useful (see below under “Engineered
Molecules”). Also, a
polymer-based molecular machine system might be used if one had been developed
previously.

Solids Built in
Machine-phase

“Machine-phase” means that all reactive molecules are controlled and moved
mechanically rather than diffusing randomly, and reactions take place under
mechanical control. Deposition of atoms and inducing of reactions in vacuum has
already been accomplished. A complete set of reactions for vacuum deposition of
arbitrary shapes in a covalent solid has not yet been worked out and verified,
but there are quite a few covalent solids that would be useful to build due to
their excellent material properties, including diamond, silica, alumina
(sapphire), and cubic boron nitride.

This approach to building nanoscale tools may be unfamiliar to chemists and
molecular biologists, but may be a better fit than most nanoscale techniques for
today's mechanical engineering disciplines.[ix]
If cleanliness can be maintained, it may be possible to take advantage of
superlubricity between stiff surfaces.[x]
Mechanical transport may be faster and more predictable than diffusive
transport. Absence of fluids could reduce drag, increasing efficiency and
improving performance through higher speeds. High density of strong covalent
bonds in some materials implies superior material properties. Although it is too
early to say with confidence which of these theoretical benefits will be
practically useful, they are certainly attractive targets. (Some of these
benefits may be available to systems built in solution and then dried.)

Investigation to date on machine-phase synthesis of covalent solids has focused
on reactions that deposit just one or a few atoms per operation. This would
require many operations to build a complete nanoscale manufacturing tool, and
this could be difficult to achieve with macro-scale scanning probe
microscopes—especially given the ultra-clean conditions needed to prevent some
of the proposed highly reactive “tool tips” from being spoiled by contact with
random molecules. MEMS scanning probes, or even specially built NEMS systems
(perhaps made with ion etching), could reduce this problem. An intermediate tool
also might be built using one of the solution-phase methods. The smaller the
tool, the faster it could work, and the less volume would have to be kept clean.
Also, if actuators can be made on the same size scale as the tool tip, then more
actuators may be included to make a more flexible and functional tool.

Integrated
Molecular Manufacturing

A far-term goal of molecular manufacturing research is to build not just a large
mass of products, but large integrated products. Sufficiently large products
would create the possibility of manufacture for direct human use, without
further expensive manufacturing steps, and the integration of familiar user
interfaces. Several problems would have to be solved in order to achieve this. A
preliminary high-level description of possible solutions for some of these
problems for a single hypothetical technology filled an eighty-page paper[xi].
This section very briefly summarizes that work.

In any system containing huge numbers of nanoscale components, some will be
defective. It appears that, at least for simple hierarchical designs, the use of
simple redundancy at multiple levels can result in excellent aggregate
reliability. For example, if a device has less than a 3% chance of failing in a
certain time period, then a group of eight devices plus one spare will have
higher reliability than a single device. Multiple levels of such redundancy can
make the aggregate failure rate negligible at a modest cost in extra mass.

To produce an integrated product, it helps to have the production stations
fastened into a framework so that the position of each nanoscale partial product
is known. The framework can also be used to deliver power and control, and
separate the workspace from the feedstock and cooling channels. (Waste heat
appears to be a significant but not insurmountable problem, which will
presumably improve in less primitive designs.) With strong materials, the mass
of the framework may be a fraction of the mass of the active components.

To produce a heterogeneous product, the manufacturing systems must be
individually controlled. The instructions may be delivered through a simple
hierarchical network, but probably must be processed locally. This would require
nanoscale computers, which would be responsible for significant portions of the
mass and power budget. (Commonly used molecular pieces could be built by
special-purpose high-speed systems—mills—substantially reducing the
required control inputs.)

Nanoscale subproducts must be joinable to make a large product. With the high
speed implied by small size, each workstation could fabricate millions of
mechanical features. This should make it possible to build mechanical fastening
systems into each subproduct, facilitating the task of joining them. (In some
systems, chemical reactions may be used for joining subproducts.)

The reference technology was diamond deposition and diamondoid materials. The
nanoscale fabricator was adapted from Merkle's work, which itself was
intentionally primitive and simple[xii].
The mechanical positioning/reaction system was assumed to be actuated by
ratchets, requiring many control inputs for each motion. Despite the handicaps
imposed by primitive design, it was calculated that the proposed nanofactory
might be able to build another nanofactory—even a version twice as big—in less
than a day.

Enabling
Technologies

Several existing and projected technologies may be useful for development of the
various approaches and stages of molecular manufacturing. The following is only
a partial list. The technologies listed are useful for imaging, fabrication of
nanoscale shapes and tools, and basic research into relevant nanoscale
phenomena. Because many technologies can perform more than one function, they
are not grouped into categories.

Computers

Computers have become quite powerful and will continue to improve. Computational
chemistry is becoming increasingly trusted. Estimates can be determined of
physical properties of molecular structures. Eventually, multilevel integrated
simulations might be useful in planning and evaluating larger systems.

Computers can also be useful for some design processes. For example, recent work
on protein folding to a desired shape used a repeated simulate-and-modify
process to arrive at appropriate sequences. Appropriate DNA sequences for
optimum folding to a desired shape also have been generated by computer. As more
extensive mechanosynthetic capabilities are developed, the ability to automate
them will become crucial to carrying out repeated operations without excess
labor.

Scanning Probe
Microscopes

Scanning probe microscopes (SPMs) can image areas with atomic resolution, and
also manipulate molecules and do chemistry. Most SPMs have only a single probe
with three degrees of freedom, but Xidex Corp. is developing two-probe,
six-degree-of-freedom systems that will be able to touch the tips together[xiii].
This may be useful for research into mechanosynthetic reactions: A tip with an
active molecule could be brought together with another tip acting as a receptive
surface, at various repeatable angles and offsets, to test the effects of
displacement and angle on the reaction. SPMs can work in air, water, or vacuum,
at room temperature or cryogenic temperature. A deposition system that can
create 15-nm lines of molecules has been developed, called dip-pen
nanolithography (DPN).

Electron
Microscopes

Electron microscopes can image with near-atomic resolution. They can be used to
cut carbon nanotubes, even to trim outer tubes from multiwalled tubes[xiv].
They can also deposit a variety of materials from gas feedstock (electron beam
induced deposition, EBID). These deposits have a feature size as small as 10 nm
and can form three-dimensional structures.[xv]

Sub-wavelength
Imaging

FRET (fluorescence resonance energy transfer, which is very sensitive to
nanoscale distance) can be used to determine relative positions[xvi].
NanoSight has developed an imaging system that can be placed in an existing
optical microscope and image 20 nm particles[xvii].
AngstroVision has claimed to be developing 3D nm-scale imaging using visible
light.[xviii]
A paper at NASATech claims that imaging below the diffraction limit should be
possible with incoherent light.[xix]

Ion Etching

Ion etching systems can achieve single-atom accuracy and can use tiltable
workpieces.[xx]
This may enable production of freestanding (undercut) kinematic structures from
high-performance materials that might be useful for research into nanoscale
machinery or even as nanoscale molecular manufacturing systems.

Engineered
Molecules and Molecular Composites

DNA structures have been used to position carbon nanotubes to make a working
transistor. Protein folding prediction is still problematic, but the inverse
problem—design of sequences that will fold into a desired shape—is becoming
reliable.[xxi]

Silica can be deposited from water; this deposition can be
mediated in
shirtsleeve conditions by the enzyme silicatein.[xxii]
A silicatein molecule attached to a positioning system might be useful in
building silica structures to specified shapes.

Levins and Schafmeister have developed a new polymer that uses two bonds between
each monomer for significantly increased stiffness and well-defined shape even
without folding[xxiii].
This may make it easier to design and build desired molecular shapes.
Schafmeister states[xxiv]
that conventional
amino acids can be incorporated into the polymer chain; this increases
chemical flexibility at the expense of local stiffness.

A vast number of other molecules may be suitable for forming nanoscale
engineered structures.

Recommendations for
Study

The essence of molecular manufacturing is very simple: the formation of precise
molecular structures under direct mechanical guidance. Artificial examples of
this are close to being demonstrated, and a set of fairly short steps may lead
from there to the achievement of a useful manufacturing technology.

The mechanical component of molecular manufacturing does not require a classical
mechanical engineering approach, but such an approach seems to be a good fit for
the method—especially since the creation of designed molecules will make it
relatively easy to specify their shape.
Nanoscale
structures are often assumed to be inherently floppy and unstable, but this will be less true for strongly crosslinked polymers or covalent solids than for weakly crosslinked biological
molecules. It is worth investigating how small a mechanical structure
implemented in various materials can be made before thermal noise or quantum
effects spoil its applicability as a mechanical design element. A related
question, which has not yet been studied[xxv],
is how to design nanoscale mechanical elements to be reliable machines in the
face of thermal noise and surface forces, and how small such designs can be
made. A major and underappreciated potential advantage of molecular
manufacturing products over MEMS is that the use of atomically precise surfaces
may eliminate wear and greatly reduce friction.

There are many possible approaches to molecular manufacturing: many materials in
at least four basic processes (polymer, covalent in solvent, noncovalent in
solvent, covalent in machine-phase). Most of the possibilities have never been
studied. A study of the merits and potentials of a range of approaches and
materials would be very useful. Once the potential capabilities and products
were better understood, a more detailed roadmap to their development could be
produced.

Although low friction and low wear have been demonstrated in a few cases, the
mechanisms of nanoscale friction are not well understood.[xxvi]
The study of low-friction sliding interfaces would help in determining the
performance limits of nanoscale machinery. The study should include wet as well
as superclean interfaces, and stiff materials and surfaces as well as
biological-style non-stiff, wetted, or bushy surfaces.

Nanoscale and molecular actuators are being studied, but many of these studies
are not directed at large-scale integration of the actuators into nanoscale
machines. The complex construction promised by even basic molecular
manufacturing indicates that multi-actuator systems soon may be desirable. It
would be useful to do studies emphasizing actuators that can be integrated with
a variety of structures and that can be controlled via rapid, small, and
independent channels.

The binding and positioning of molecules will be a key competency for molecular
manufacturing. Antibodies seemingly can be developed to bind almost anything.
Binding pockets for individual molecules have been made by taking “molds” of the
molecules in plastic. It would be useful to further explore how to bind and
transport molecules, especially how to design binding sites based mainly on
steric properties (shape) that will be flexibly engineerable in molecular
manufacturing approaches.

Reliability will be an important factor in the ability to make complicated
automated manufacturing systems. The mechanosynthetic operations have not yet
been selected, but it may be possible to estimate upper and lower bounds on
classes of operation, or at least begin to understand what factors affect
reliability. Preliminary arguments indicate that reliabilities between 109
and 1015 may be achievable.[xxvii]
If and when massively parallel systems are built, fault tolerance will be
required. More detailed study of fault tolerant systems would help.

As results from the above studies become available, it will be possible to form
preliminary estimates of the manufacturing throughput and product capabilities
of a particular molecular manufacturing technology. It would be useful to start
such studies today, for two reasons. First, preliminary answers to many of the
above questions are already available for at least one technology. Second,
attempts to quantify performance will show what other questions need to be
studied.

Any estimate of the time and resources that would be required to develop any
particular approach to any given level will necessarily be preliminary. However,
it seems important to develop such estimates as soon as possible. Exponential
molecular manufacturing may significantly impact the semiconductor and
pharmaceutical industries, among others; and integrated molecular manufacturing
may even be competitive as a general-purpose manufacturing technology. This
implies that development of molecular manufacturing may have a very high payoff.
The basic ideas have been in the literature for over two decades[xxviii]
and a quantitative analysis of the extremely high potential performance of one
approach was published in 1992.[xxix]The continuing
development of enabling technologies, as well as the rapidly advancing theory of
molecular manufacturing, increase the possibility increases that an all-out Manhattan Project-like effort
will be launched by some government or large corporation.[xxx]
The likelihood of this cannot be estimated without an improved understanding of
what will be required to develop a given capability.

Conclusion

Molecular manufacturing relies on two counterintuitive ideas: first, that
mechanical operations can reliably be carried out at the nanoscale; second, that
handling of individual molecules can be scaled up to produce useful quantities
of product. On closer examination, these ideas appear to be supportable; this
indicates that molecular manufacturing may have been underappreciated and may
deserve more focused attention.

The development of molecular manufacturing can be an incremental process from
today's capabilities. Although the most exciting results rely on the most
advanced and integrated capabilities, even the earliest products of basic
molecular manufacturing could be useful for basic research and for components
such as sensors.

There are several specific areas of study that can advance our understanding of
the potential of the approach. These studies can and should be initiated today.

[ix] Although the
lower size limits of mechanical engineering (the point where classical
approximations give way to quantum effects) are not known, preliminary
analysis indicates that structures smaller than 10 nm and perhaps
approaching 1 nm may be usefully analyzed classically. See Nanosystems
Ch. 5.

[xxv] A few studies
have been made of individual machines, such as a planetary gear; there is
room for guarded optimism.

[xxvi] M Dienwiebel
et al. 2004 Superlubricity of graphite Phys. Rev. Lett. 92 126101. Also
various work by Zettl with rotating and sliding nested carbon nanotubes.
“Friction at the nano-scale” is a recent Physics World article by a nano-tribologist
explaining how much is still unknown.
http://physicsweb.org/articles/world/18/2/9/1

[xxvii] See
Nanosystems chapter 6. Note that high reliability is possible even in
simple non-machine-phase systems; a solution-phase system that simply
increases effective concentration by many orders of magnitude at chosen
reaction sites may have a comparably low rate of unwanted reactions if
reaction energy barriers are well-chosen.